NM_005249.5:c.447C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP7BA1

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Ala149= variant in FOXG1 is 0.227% in European (Non-Finnish) sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The silent p.Ala149= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). In summary, the p.Ala149= variant in FOXG1 is classified as benign based on the ACMG/AMP criteria (BA1, BP7). LINK:https://erepo.genome.network/evrepo/ui/classification/CA232483/MONDO:0100040/016

Frequency

Genomes: 𝑓 0.0010 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 7 hom. )

Consequence

FOXG1
NM_005249.5 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:11

Conservation

PhyloP100: -0.189

Publications

1 publications found

Variant links:

Genes affected

FOXG1 (HGNC:3811): (forkhead box G1) This locus encodes a member of the fork-head transcription factor family. The encoded protein, which functions as a transcriptional repressor, is highly expressed in neural tissues during brain development. Mutations at this locus have been associated with Rett syndrome and a diverse spectrum of neurodevelopmental disorders defined as part of the FOXG1 syndrome. This gene is disregulated in many types of cancer and is the target of multiple microRNAs that regulate the proliferation of tumor cells. [provided by RefSeq, Jul 2020]

FOXG1 links:

LINC01551 (HGNC:19828): (long intergenic non-protein coding RNA 1551)

LINC01551 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP7

For more information check the summary or visit ClinGen Evidence Repository.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXG1	NM_005249.5 link	c.447C>T	p.Ala149Ala	synonymous_variant	Exon 1 of 1	ENST00000313071.7	NP_005240.3	P55316

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FOXG1	ENST00000313071.7 link	c.447C>T	p.Ala149Ala	synonymous_variant	Exon 1 of 1	6	NM_005249.5	ENSP00000339004.3	P55316
FOXG1	ENST00000706482.1 link	c.447C>T	p.Ala149Ala	synonymous_variant	Exon 2 of 2			ENSP00000516406.1	P55316
LINC01551	ENST00000675861.1 link	n.374+1713C>T		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.00100

AC:

150

AN:

149694

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000294

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000133

Gnomad ASJ

AF:

0.000291

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000431

Gnomad FIN

AF:

0.000392

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00190

Gnomad OTH

AF:

0.000486

GnomAD2 exomes

AF:

0.00108

AC:

142

AN:

131114

AF XY:

0.00100

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000368

Gnomad ASJ exome

AF:

0.000381

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000357

Gnomad NFE exome

AF:

0.00235

Gnomad OTH exome

AF:

0.000493

GnomAD4 exome

AF:

0.00183

AC:

2504

AN:

1364848

Hom.:

Cov.:

AF XY:

0.00185

AC XY:

1247

AN XY:

672992

show subpopulations

African (AFR)

AF:

0.000128

AC:

AN:

31368

American (AMR)

AF:

0.000449

AC:

AN:

35612

Ashkenazi Jewish (ASJ)

AF:

0.000443

AC:

AN:

24818

East Asian (EAS)

AF:

0.00

AC:

AN:

35664

South Asian (SAS)

AF:

0.000356

AC:

AN:

78590

European-Finnish (FIN)

AF:

0.000419

AC:

AN:

33444

Middle Eastern (MID)

AF:

0.00124

AC:

AN:

4024

European-Non Finnish (NFE)

AF:

0.00223

AC:

2370

AN:

1064270

Other (OTH)

AF:

0.000981

AC:

AN:

57058

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.527

Heterozygous variant carriers

168

336

504

672

840

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

188

282

376

470

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00100

AC:

150

AN:

149804

Hom.:

Cov.:

AF XY:

0.000807

AC XY:

AN XY:

73140

show subpopulations

African (AFR)

AF:

0.000293

AC:

AN:

40994

American (AMR)

AF:

0.000133

AC:

AN:

15064

Ashkenazi Jewish (ASJ)

AF:

0.000291

AC:

AN:

3434

East Asian (EAS)

AF:

0.00

AC:

AN:

4994

South Asian (SAS)

AF:

0.000431

AC:

AN:

4638

European-Finnish (FIN)

AF:

0.000392

AC:

AN:

10206

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.00190

AC:

128

AN:

67206

Other (OTH)

AF:

0.000481

AC:

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000801

Hom.:

Bravo

AF:

0.000963

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:3

Sep 11, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

FOXG1: BP4, BP7 -

Rett syndrome, congenital variant

Benign:3

Aug 02, 2017

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:2

Jun 22, 2017

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 28, 2016

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Sep 07, 2016

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

FOXG1 disorder

Benign:1

Aug 25, 2022

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The allele frequency of the p.Ala149= variant in FOXG1 is 0.227% in European (Non-Finnish) sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The silent p.Ala149= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). In summary, the p.Ala149= variant in FOXG1 is classified as benign based on the ACMG/AMP criteria (BA1, BP7). -

FOXG1-related disorder

Benign:1

Aug 27, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.97

PhyloP100

-0.19

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over